By Arzo Hamidi, PharmD, BCCCP
Clinical Pharmacy Specialist, Adult Critical Care, Rush University Medical Center, Chicago
SYNOPSIS: There is a lower risk of bleeding with apixaban during the treatment of venous thromboembolism compared to warfarin in patients with end-stage kidney disease.
SOURCE: Ellenbogen MI, Ardeshirrhouhanifard S, Segal JB, et al. Safety and effectiveness of apixaban versus warfarin for acute venous thromboembolism in patients with end-stage kidney disease: A national cohort study. J Hosp Med 2022;17:809-818.
The choice of therapeutic anticoagulation (AC) agent is a patient-specific decision. The search for safer and more efficacious agents continues. This new-user, active comparator retrospective cohort study of adult patients with end-stage kidney disease (ESKD) on dialysis between 2014 and 2018 evaluated the treatment of venous thromboembolism (VTE). From a national database that collects and distributes information about chronic kidney disease (CKD) and ESKD, data were collected on patients with fee-for-service Medicare as their primary insurance. VTE was defined using International Classification of Disease (ICD)-9 and ICD-10 codes from 30 days before to seven days after the initial prescription for warfarin or apixaban. Patients with atrial fibrillation (AF) were excluded.
The primary outcome was major bleeding within six months of AC initiation, defined as either bleeding associated with death or critical site bleeding requiring hospitalization or bleeding at any site requiring hospitalization with transfusion. Secondary outcomes were clinically relevant nonmajor episodes of bleeding. Follow-up continued for six months or until disenrollment from Medicare, kidney transplantation, hospice, or death. Analysis was based on the principle of intent-to-treat. A propensity score was generated for each cohort.
In total, there were 2,302 patients in the apixaban cohort and 9,263 in the warfarin cohort. The mean age was 59.8 years and 58.3 years for apixaban and warfarin, respectively. There were 45.9% and 44.6% white patients, and 55.3% and 54.1% females in the apixaban and warfarin groups, respectively. About 94% of patients required hemodialysis, and 6% required peritoneal dialysis. Half of patients filled 5 mg tablets and 40% filled exclusively 2.5 mg tablets, with the remaining patients using a combination of the tablet strengths. Overall, total major bleeding occurred in 13% of the patients, with 10.3% in the apixaban group vs. 13.7% in the warfarin group (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.7-0.94). Intracranial bleeding was 1.8% in the apixaban group and 2.5% in the warfarin group (HR, 0.69; 95% CI, 0.48-0.98). Gastrointestinal bleeding occurred in 8.6% of the apixaban group and 10.4% of the warfarin group (HR, 0.82; 95% CI, 0.69-0.96). Recurrent VTE incidence or mortality was not statistically significantly different between groups.
COMMENTARY
During the study time frame, the use of apixaban increased heavily from 2% of patients in the study in 2014 to 47% by 2018. This shows that there is a change in practice with the growing use of apixaban for VTE treatment in this patient population in recent years. A published systematic review from 2021 concluded that apixaban had a lower incidence of bleeding compared to warfarin and no significant difference in recurrent VTE. Of note, this systematic review did mention that there are no data to safely support rivaroxaban or dabigatran as alternative oral anticoagulants for the treatment of VTE.1
The included patient population was a narrow but specific group to allow evaluation of these safety and efficacy outcomes. The other exclusion criteria beside patients with atrial fibrillation included patients admitted to hospice and patients with any AC use in the 30 days prior to cohort entry to prevent confounding factors. Such exclusion criteria allowed for longer-term follow-up and minimization of confounding factors.
The dosing strategies for VTE treatment were mentioned but unable to be further explored. The majority of patients received 5 mg tablets, with presumed instructions to take the recommended dose of 5 mg twice daily per the package insert; however, a large number of patients received 2.5 mg tablets. The 2.5 mg twice daily dosing for VTE is an off-label dose. For patients who received these tablet sizes, specific administration instructions are unknown. Also, it is unclear if the reported safety and efficacy outcomes are dose-dependent effects. It would be helpful for future studies to evaluate the dosing strategies. Another area for future studies would be determining if patients received parenteral anticoagulation first and how loading doses were managed. For VTE treatment, it is recommended to receive a loading dose period of seven days with 10 mg twice daily for apixaban. The optimal duration of loading doses when transitioning from parenteral anticoagulation to apixaban remains unclear (i.e., counting parenteral anticoagulation toward the seven days of loading or always prescribing seven days of apixaban loading doses).
Potential advantages with the use of apixaban compared to warfarin include less therapeutic drug monitoring and no requirement to bridge with a parenteral anticoagulant. Overall, data show that apixaban is a safe alternative to warfarin for VTE treatment in patients with ESKD.
REFERENCE
- Cheung CYS, Parikh J, Farrell A, et al. Direct oral anticoagulant use in chronic kidney disease and dialysis patients with venous thromboembolism: A systematic review of thrombosis and bleeding outcomes. Ann Pharmacother 2021;55:711-722.
